Pancreas Volume in Preclinical Type 1 Diabetes

描述（由申请人提供）：几十年来，1型糖尿病（T1D）一直被认为是一种由产生胰岛素的胰腺β细胞的自身免疫性破坏引起的疾病。在新发T1D和已确诊的T1D患者中，胰腺普遍萎缩，这一点通常不太被重视，但事实上同样得到了充分证实。申请人最近的研究表明，来自患有T1D的器官供体的胰腺重量显著降低。然而，更重要的是，在仅具有单一糖尿病相关自身抗体的器官供体中也观察到胰腺重量的减少。这些研究结果强调，胰腺重量的变化可能代表T1D发病机制中的早期事件，并提出了一个有趣的想法，即胰腺体积可能作为长期期望的“生物标志物”，用于了解疾病预测和进展。该申请寻求试点研究的资金，以确定胰腺体积的非侵入性估计是否可用作监测自身抗体阳性的T1D患者一级亲属的预后工具。我们假设T1D与进行性胰腺萎缩相关，胰腺萎缩与功能性β细胞群相关。我们建议在四个研究组中检查胰腺体积：对照组（年龄和性别与自身抗体阳性参与者匹配），单一自身抗体阳性参与者，多种自身抗体阳性参与者和近期发作的T1D患者。将通过NIH TrialNet“预防途径”研究和佛罗里达大学糖尿病中心的儿科和成人内分泌科招募受试者。具体目标包括：1）利用 非侵入性放射成像，以确定对照受试者、T1 D风险增加的受试者（单一和多种自身抗体阳性组）和新发T1 D受试者的胰腺体积。将通过两种无创放射学方法（超声（US）和磁共振成像（MRI））评估胰腺体积。2)胰腺体积与β细胞功能和自身免疫相关。这一目的旨在确定β细胞功能的生物标志物（空腹血糖，C肽和HbA1c）和T1D风险（自身抗体）是否与胰腺体积相关。3)胰腺体积与T细胞功能亚群及HLA相关性研究最终目的是确定T细胞亚群功能研究和HLA类型是否可用于解释对照组、高危受试者和新发T1D受试者之间胰腺体积的差异。该提案的创新方面包括应用一种高度可及，非侵入性和相对低成本的成像方法来评估T1D发病机制，以及免疫学，病理学，临床内分泌学（儿科和成人内分泌学），生物统计学和放射学教师的组合，以形成一个高度互动和互补的研究团队。如果胰腺体积可以随着时间的推移进行监测，并且能够识别与胰腺体积的特定阈值相一致的功能性β细胞质量的特定损失，则胰腺体积可以代表用于T1D风险患者的临床预防和干预试验的其他生物标志物的主要补充。同样，随着时间的推移监测胰腺体积可以作为疾病进展的准确，无创和简单的替代标志物，从而允许及时和指导性的临床护理。

DESCRIPTION (provided by applicant): For decades, type 1 diabetes (T1D) has been considered a disorder resulting from the autoimmune destruction of insulin producing pancreatic beta cells. What is often less appreciated, but is in fact equally well established, is the generalized atrophy of the pancreas in new onset T1D as well as in those with established disease. Recent studies by the applicants demonstrated that pancreas weight from organ donors with T1D was significantly reduced. However, and more profound, reductions in pancreas weight were also observed in organ donors with only single diabetes-related autoantibodies. These findings underscore that changes in pancreas weight may represent an early event in the pathogenesis of T1D and raise the intriguing idea that pancreatic volume may serve as a long desired "biomarker" for understanding both disease prediction as well as progression. This application seeks funding for a pilot study to determine whether noninvasive estimations of pancreas volume can be used as a prognostic tool in monitoring autoantibody positive, first-degree relatives of patients with T1D. We hypothesize that T1D is associated with progressive pancreatic atrophy that correlates with functional beta cell mass. We propose to examine pancreas volume in four study groups: controls (age and gender matched to autoantibody positive participants), single autoantibody positive participants, multiple autoantibody positive participants, and recent onset T1D patients. Subjects will be recruited through the NIH TrialNet "Pathway to Prevention" studies and the Pediatric and Adult Endocrinology units at the University of Florida Diabetes Center. Specific aims include: 1) Utilize noninvasive radiological imaging to determine pancreas volume in control subjects, subjects at increased risk for T1D (single and multiple autoantibody positive groups), and subjects with new onset T1D. Pancreas volume will be assessed by two noninvasive radiological methods, ultrasound (US) and magnetic resonance imaging (MRI). 2) Correlate pancreas volume with beta cell function and autoimmunity. This aim seeks to determine if biomarkers of beta cell function (fasting glucose, C-peptide and HbA1c) and T1D risk (autoantibodies) correlate with pancreas volume. 3) Correlate pancreas volume with T cell function subsets and HLA. This final aim seeks to determine whether T cell subset functional studies and HLA types can be utilized to explain variance in pancreatic volume amongst controls, at risk subjects, and subjects with new onset T1D. Innovative aspects of this proposal include application of a highly accessible, noninvasive, and relatively low cost imaging method to assess T1D pathogenesis and the combination of faculty in immunology, pathology, clinical endocrinology (pediatric and adult endocrinology), biostatistics, and radiology to form a highly interactive and complementary research team. If pancreatic volume could be monitored over time and one is able to identify a specific loss of functional beta cell mass which coincides with a certain threshold of pancreas volume, pancreas volume could represent a major complement to other biomarkers used for clinical prevention and intervention trials for patients at risk for T1D. As well, monitoring pancreatic volume over time could function as an accurate, noninvasive, and simple surrogate marker for disease progression, allowing timely and guided clinical care.